Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

Christopher S Smillie; Moshe Biton; Jose Ordovas-Montanes; Keri M Sullivan; Grace Burgin; Daniel B Graham; Rebecca H Herbst; Noga Rogel; Michal Slyper; Julia Waldman; Malika Sud; Elizabeth Andrews; Gabriella Velonias; Adam L Haber; Karthik Jagadeesh; Sanja Vickovic; Junmei Yao; Christine Stevens; Danielle Dionne; Lan T Nguyen; Alexandra-Chloé Villani; Matan Hofree; Elizabeth A Creasey; Hailiang Huang; Orit Rozenblatt-Rosen; John J Garber; Hamed Khalili; A Nicole Desch; Mark J Daly; Ashwin N Ananthakrishnan; Alex K Shalek; Ramnik J Xavier; Aviv Regev

doi:10.1016/j.cell.2019.06.029

Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

Cell. 2019 Jul 25;178(3):714-730.e22. doi: 10.1016/j.cell.2019.06.029.

Authors

Christopher S Smillie¹, Moshe Biton², Jose Ordovas-Montanes³, Keri M Sullivan⁴, Grace Burgin¹, Daniel B Graham⁵, Rebecca H Herbst⁶, Noga Rogel¹, Michal Slyper¹, Julia Waldman¹, Malika Sud¹, Elizabeth Andrews⁴, Gabriella Velonias⁴, Adam L Haber¹, Karthik Jagadeesh¹, Sanja Vickovic¹, Junmei Yao⁷, Christine Stevens⁸, Danielle Dionne¹, Lan T Nguyen¹, Alexandra-Chloé Villani⁹, Matan Hofree¹, Elizabeth A Creasey⁷, Hailiang Huang¹⁰, Orit Rozenblatt-Rosen¹, John J Garber⁴, Hamed Khalili⁴, A Nicole Desch¹¹, Mark J Daly¹², Ashwin N Ananthakrishnan¹³, Alex K Shalek¹⁴, Ramnik J Xavier¹⁵, Aviv Regev¹⁶

Affiliations

¹ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
² Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Molecular Biology, MGH, Boston, MA, USA.
³ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Division of Infectious Diseases and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
⁴ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA.
⁵ Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA.
⁶ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁷ Center for Computational and Integrative Biology, MGH, Boston, MA, USA.
⁸ Broad Institute, Cambridge, MA, USA.
⁹ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA.
¹⁰ Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA.
¹¹ Broad Institute, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA.
¹² Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
¹³ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA. Electronic address: aananthakrishnan@mgh.harvard.edu.
¹⁴ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Electronic address: shalek@mit.edu.
¹⁵ Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA. Electronic address: xavier@molbio.mgh.harvard.edu.
¹⁶ Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA. Electronic address: aregev@broadinstitute.org.

Abstract

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4⁺ enterocytes, microfold-like cells, and IL13RA2⁺IL11⁺ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

Keywords: anti-TNF resistance; cell-cell interactions; colon; genome-wide association studies; inflammation; inflammatory bowel disease; large intestine; single-cell RNA-seq; single-cell genomics; ulcerative colitis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antibodies, Monoclonal / therapeutic use
Bestrophins / metabolism
CD8 Antigens / metabolism
Case-Control Studies
Colitis, Ulcerative / drug therapy
Colitis, Ulcerative / metabolism
Colitis, Ulcerative / pathology*
Colon / metabolism*
Colon / pathology
Enterocytes / cytology
Enterocytes / metabolism
Female
Genetic Loci
Genome-Wide Association Study
Humans
Interleukin-17 / metabolism
Male
Middle Aged
Risk Factors
T-Lymphocytes / cytology
T-Lymphocytes / metabolism
Thrombospondins / metabolism
Tumor Necrosis Factor-alpha / immunology
Tumor Necrosis Factor-alpha / metabolism
Young Adult

Substances

Antibodies, Monoclonal
BEST4 protein, human
Bestrophins
CD8 Antigens
Interleukin-17
RSPO3 protein, human
Thrombospondins
Tumor Necrosis Factor-alpha

Abstract

Publication types

MeSH terms

Substances

Grants and funding